A Systematic Review of Phytochemistry, Nutritional Composition, and Pharmacologic Application of Species of the Genus Viola in Noncommunicable Diseases (NCDs)

Viola L. is the largest genus of the Violaceae family with more than 500 species across the globe. The present extensive literature survey revealed Viola species to be a group of important nutritional and medicinal plants used for the ethnomedicinal treatment of noncommunicable diseases (NCDs) such as diabetes, asthma, lung diseases, and fatigue. Many plant species of this genus have also received scientific validation of their pharmacological activities including neuroprotective, immunomodulatory, anticancer, antihypertensive, antidyslipidemic, analgesic, antipyretic, diuretic, anti-inflammatory, anthelmintic, and antioxidant. Viola is highly rich in different natural products some of which have been isolated and identified in the past few decades; these include flavonoids terpenoids and phenylpropanoids of different pharmacological activities. The pharmacokinetics and clinical studies on this genus are lacking, and the present review is aimed at summarizing the current understanding of the ethnopharmacology, phytochemistry, nutritional composition, and pharmacological profile of medicinal plants from the Viola genus to reveal its therapeutic potentials, gaps, and subsequently open a new window for future pharmacological research.


Introduction
Medicinal plants have been explored from time immemorial as a source of healing agents against several diseases and have been subjected to scientifc analysis for the validation of their efcacy against several human diseases [1 -13].Te family Violaceae comprises about 500 species distributed across 20 genera [14].Te plant is popular in the northern part of the world as Zihua Diding [15] and is used traditionally by ancient Chinese against furuncles, carbuncles, and boils [16].Diferent species of Viola are widely distributed in diferent geographical locations; seventeen Viola cinerea Boiss: Annual or perennial herb, erect or ascending, up to 20 cm tall; stems glabrous to densely pubescent.Leaves with lamina narrowly ovate or narrowly lanceolate, up to 30 × 14 mm [28].Viola difusa Gingins: It has a slightly 2-lobed stigma, long stolon with rosulate leaves at the apex, purplish fowers, a short corolla spur, and pubescent leaf blades [29].Viola bifora Linn: this species is glabrous or pubescent.Te stem is usually erect, 7.5-25 cm.leaves 2-3, kidney shaped, 2-2.5 cm.across crinate, stipules, ovate, or oblong.Flowers 1 or 2, with the same stalk, pale yellow, lower petals streaked to black, spur very short, and stigma two lobbed [30].Viola patrinii DC: it is glabrous or pubescent with short stems, tufted leaves that are triangular, usually narrowly elongated, 3.8-6.3by 1.3-3.8cm long.Te fowers are usually dark lilac and often scented [31].Viola tricolor L.: the style and stigma have visible hollow, hairs, and papillae on stigma lip.It has a flamentless stamens, visible anther appendix, and lateral anther hairs [32].Viola betonicifolia Smith: it is a perennial herb, and its height is from 8 to 20 cm.Distinguishing characteristics of this species are that it is longer in length, slim, has arrow-shaped leaves, which is usually enlarged from the base, possesses no stem, and is 6 cm (in length with a Vshaped sinus at the base).Te length of lamina is mostly 1-8 cm with a width of 5-25 mm.Te leaf margins of this plant are entirely or marginally serrate.Linear stipules are present which are fused with the petiole and may be entire or laciniate.Te sepals are 3.5-7 mm long.Te color of the petals is violet but can also be whitish.Petals are 8.5-14 mm long.Te plant taste is a little bit piquant and has a spicy fragrance [20].Te seeds are rounded-ovate, smooth, and shiny [25].Te fowers of this plant are shadowed through small pale brown pods with tiny blackish seeds.Te roots and rhizome are slender, unbranched, and short, respectively [23].Viola canescens Wall: it is subglabrous or hairy, almost perennial prostrate herb.Its roots are cylindrical, profusely branched as well as long.Leaves are broad, ovate, and reniform and may be cordate to acute tips.Leaf margins are serrate or crenate.Te length of the leaf petiole is almost twice the length of the lamina.
Evidence-Based Complementary and Alternative Medicine Leaves are pubescent and stipules are freely present.Te approximate width and length of lanceolate leaves are 5.0-20.0 and 1.0-3.0mm.At the base, they are reddish.Stems are absent.Flowers are deliberate with the size of 1.0-1.8cm approximately.Te colors of its fowers range from pale violet to violet and often almost white.Lateral spur is almost 10 mm in length.Sepals are 5 in number and are almost 2 mm wide, dentate near its base.Petals are up to 15 mm long and their width is 4.0 mm.Other characteristics of the petals include obtuse and obovate tips, and the two upper petals are wedge-shaped, and the two lateral petals are narrow and hairy at their base and dark clear streaks are found on them.Himalayan white violet's style is club-shaped and the ovary shape is ovate with hairs [33].
Viola pilosa Blume: this specie is peculiar within V. ser.Serpentes (W.Becker) steen is a group of about ten species mainly distributed in the southern and southeastern part of Asia, is characterized by an acaulescent stoloniferous habit [34].
3.1.Chemical Constituents.Viola is highly rich in diferent natural products out of which about 200 compounds have been isolated and identifed in the past few decades; these include favonoids, coumarins, alkaloids, triterpenoids, saponins, anthocyanins, phenols, tannins, phytosterols terpenoids, lignans, sesquiterpenes, cyclotides, and phenyl propanoids of diferent pharmacological activities such as antibacterial, antioxidant, anti-infammatory, and antihypertensive efects among others [35].Tis is as evidenced by studies demonstrating that the ethanolic and methanolic extract tested positive to diferent phytochemicals.Table 1 shows the chemical constituents of six species of Viola.

Essential Oils of Viola.
Essential oils are compounds of known antioxidant, antibacterial, and antiseptic properties which can be extracted from the plant by hydrodistillation solvent extraction method complemented with gas chromatography mass spectrometer analysis.Analysis of a species of Viola essential oils revealed the presence of mainly butyl-2-ethylhexylphthalate and 5,6,7,7a-tetrahydro-4,4,7atrimethyl-2(4H)-benzofuranone.Essential oils are generally used in the perfumery industry [36], while the pigment extract from the fowers are used for litmus testing strips and in making excellent ground cover [37].Several reports have documented the compounds isolated and identifed in the essential oils of Viola.V. odorata contained the highest number of isolated compounds while lower compounds were identifed from V. thianschanica.Te sesquiterpenes and aliphatic compounds formed the predominantly isolated compounds in the various species but were not isolated from V. thianschanica species.Tese constituents are presumably due to the diferent location and/or time of collection of the plant.Bioactive compounds identifed in Viola are shown in Table 2.

Traditional Uses
Tere is a high demand of medicinal plants for improved quality of life [38,39].Te biodynamic compounds found in medicinal plants are of important analeptic value [43,45] rich sources of fuel, fodder, and timber.Various side efects accompany diferent kinds of commercial drugs which have led to the increase in the use of safe, cheap, and efective herbal remedies for diferent ailments [44].Te folk people of Pakistan (in Swat, Hazara, and Dir districts), India, Nepal, Sri Lanka, China, Malaysia, and Australia used V. betonicifolia in the treatment of pyrexia, astringent, cancer, purgative, and neurological disorders [46], skin, sinusitis, blood disorders, and pharyngitis [47], the roots in the treatment of respiratory and kidney diseases, fowers for respiratory diseases such as asthma, cough, and colds and the leaves for boils [40].
Viola tricolor has been used traditionally against skin disorders.Heartsease (Viola tricolor L.) has been used for centuries in Europe against infammatory lung and skin disorders and psoriasis [41,42].Several handbooks of phytotherapy have reported traditional use of Viola [52] such as in the German commission E Monograph (phytotherapy and herbal substances) of the German Federal Institute for Drugs and Medical Devices [48] and in the Pharmacopoeia [49].Te ethnomedicinal uses of Viola are shown in Table 3.

Nutritional Composition.
Te macronutrients and micronutrients required for a healthy living can be obtained via the consumption of plants.Over 30, 000 wide edible plants (WEPs) have been identifed around the globe as potential nutrient supply, one of them is the Viola species [50].Te edible fowers Viola species are used in cuisines, desserts, and beverages majorly due to their diferent colors, shapes, and favors [51].Nutritional and chemical characterizations of edible petals and corresponding infusions of Viola species are used for valorization as new food ingredients.Although, some of the species are not currently used in food and thus considered unconventional food plants; however, their rich nutritional and bioactive content make them display a positive efect on health [53,54].Previous study reported that 100 g of dry sample of Viola x Wittrockiana contained a total carbohydrate, crude protein, fat, and ash content of 80.27 g, 10.14 g 1.67 g, and 7.92 g, respectively, with a total energy value of 376.67 kcal [55].
Viola betonicifolia plant powder was reported to be a potential excellent source of nutrient and food supplement as it contained fats, proteins, carbohydrates, fber, and vitamin C [23,67].Fernandes et al. [68] reported diferent nutritional content of three diferent varieties of Viola x Wittrockiana colors (white, red, and yellow) at diferent developmental stages.Tey found that a 100 g fresh weight of white and yellow species had a higher protein content of more than 2.00 g, the red specie had the highest carbohydrate content of 8.0 g while the fatty acids; linoleic acid (more predominant), palmitic, and linolenic acid were present in all [68].During the fowering stage, an increase in Evidence-Based Complementary and Alternative Medicine (a)

Pharmacological Activities
Viola has numerous pharmacologically activities which have been scientifcally proven by the acclaimed traditional use against microbial infections, hypertensive, HIV, pyrexial, infammatory, plasmodial, diuretic, cancer, and so on [20,26].Tese activities can be attributed to the phytochemical constituents that can be harvested and utilized for drug development for both clinical and commercial purposes.

Antioxidant Activity.
Antioxidants are usually of plant origin; they help neutralize, lessen, or scavenge the deleterious efect of free radicals in disease conditions.Te phytochemicals contain compounds that prevent free radical production or activation of detoxifying protein [69].Report shows the in vitro efect of all extracts in antioxidant study [70].Te aqueous extract of the Viola odorata fower showed the antioxidant potential of 2,2-diphenyl-1-picrylhydrazyl radical [69].Both chloroform and methanolic extracts of V. odorata showed antioxidant activity by stalling the bleaching assays of β-carotene/linoleic acid and 2,2diphenyl-1-pycril hydrazyl (DPPH).Antioxidant activity was not observed in the essential oil [36].Moreover, the antioxidant activity of V. odorata extracts (DCM, ethyl acetate, ethanolic, and aqueous) tested by DPPH scavenging activity, metal chelating capacity, ferric, and phosphomolybdenum-reducing antioxidant potential displayed low to moderate activities [71].

Laxative and Diuretic Activities.
Crude ethanolic extract of V. canescens leaves was demonstrated to possess laxative activity in BALB/c mice using the charcoal meal paradigm in a dose-dependent and methanolic extract of Viola serpense.Alcoholic and aqueous extracts at 200 mg/kg and 400 mg/kg, respectively, have signifcant laxative efects [72].
Te diuretic study of n-hexane, butanol, methanolic, and aqueous extracts at doses of 200 and 400 mg/kg body weight showed the presence of favonoids in the diferent extracts.Te aqueous extract possesses diuretic property at 400 mg/kg which is indicated by increased potassium and sodium ion levels in urine production.Te highest dose exhibited good results in all extracts in the frst 5 hours and after 24 hours nhexane and methanolic extracts showed the best results.Flavonoid glycosides are reported to have diuretic activity and may be assumed for the extracts' diuretic activity [73].

Anticoagulant Activity.
Dietary rich anticoagulants or phytochemicals have been scientifcally reported to decrease thromboembolic disease occurrence, thus potentiating Viola as a good anticoagulant [74,75].Viola yedoensis Makino is used traditionally by the Chinese to treat furuncle, carbuncles, release toxic heat, anti-infammatory, and as

Species
Medicinal uses

V. patrinii
Te fower is used treatment for cough, cold and as antipurgative, while the whole plant is used by the Chinese medical system to treat cancer [56] V. canescens Te whole plant is traditionally used mostly for antipyretic, anticancer and analgesic treatment [57] V. serpens Te whole plant is traditionally used as analgesic, antitumor, antihemorroids, anti-infammatory, increased perspiration, and some respiratory diseases [58] V. bifora Te whole plant is traditionally used antimicrobial agents, analgesic, antihemorroids, anti-infammatory, increased perspiration, against constipation, and intestinal pain respiratory and skin diseases [59] V. arvensis Te stem, leaves, fowers, fruits and seeds are used as against infammation, respiratory and skin diseases, analgesic, and urinary tract infection [60] V. tricolor Te stem, leaves, fowers, fruits, and seeds are used against skin conditions, cystitis, rheumatism, bronchitis and against infammation, cough, and diuretic [60] V. odorata Fresh leaves are used for treatment of cancer, dried fowers decoction as analgesic and expectorants, seeds are used to improve removal of waste from the body, plant poultice as analgesic and against weakness [37], chewed leaves are used for anticancer, diaphoretic, febrifuge, infantile disorder, and lung troubles [61], and leaves and fowers are used for respiratory disorders [62] V. hondoensis Te whole plant is used as antidiuretic, anti-infammatory, expectorants, and for skin disease treatment [63]

V. falconeri
Te roots are used in jaundice and fowers for cough and cold [64]

V. cinerea
Te whole plant is used as an aphrodisiac [65] V. betonicifolia Te whole plant is used as an astringent, diaphoretic, antipyretic, anticancer, purgative, and some neurological disorders [66].Te fower and leaves are used for sinusitis, skin, respiratory, and blood disorders [47], for constipation and improve waste removal [40], while the roots and fruits are used for kidney and respiratory diseases and leaves are used to treat furuncle [40] 6 Evidence-Based Complementary and Alternative Medicine antisnake venom [76].Traditional Chinese herbal medicine used it against Helicobacter pyloria [77] and HIV [78].Te anticoagulant activities of three (3) new isolates of dicoumarin; dimeresculetin, euphorbetin, and esculetin identifed from V. yedoensis Makino may be as a result of activation of partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time, potentiating Viola yedoensis Makino as a potential anticoagulating drug [79].
5.4.Anticancer Activity.Flowers, leaves, and stems of V. canescens were reported as a pharmacological tool for antitumor due to the presence of cycloviolacin.Cycloviolacin is a cyclotide in plants with antitumor properties that act by creating pores on the cell membrane for entry of substances that could then kill the cancer cells.Cyclotoxic cyclotides are chemosensitive contrary to drug-resistant breast cancer [80,81].Cyclotides are cyclopeptides of unusual structure and various biological activities [82].Vigno 5 is a natural cyclopeptide identifed from Viola ignobilis [83,84] demonstrated inhibitory efect on growing cervical cancer cells.It was also reported to signifcantly elevate caspase-3 expression, reduced antiapoptotic Bcl-2, and increased proapoptotic Bax, leading to the loss of MMP and the release of cytochrome C from the mitochondria membrane in Hela cells, which explains the membrane permeability efect [85].Activated Bax is translocated as as integrated into mitochondrial membranes in apoptotic cells [86,87].Mitochondrial damage, depolarization, MMP collapse, cytochrome C release, and caspasse-3 activation through either homologous dimerization or the promotion of mPTP formation in the inner and outer mitochondrial membranes may be caused by the overexpression of Bax and low expression of Bcl-2 [88].IC 50 values of 820 and 1850 μM of circulin B and cyclopsychotride A, respectively, were reportedly cytotoxic in mouse fbroblasts [89] while varv A and F from Viola arvensis and cycloviolacin O 2 from Viola odorata showed antitumor/cytotoxic activity.Tese antitumoric activities could be leveraged on to produce novel clinical antitumor drugs [80].Further details on the cytotoxic activities of cyclotides are reported by Göransson et al. [90].
Research is still ongoing on the use of multipurpose anticancer drugs that work by creating pores on cancer cell membranes and allowing the entry of another drug that will act on the cell [91].Tis was demonstrated by using doxorubicin drug-resistant breast cancer cells treated with cycloviolacin.Tree novel cyclotides from Psychotria leptothrysa Miq.var.longicarpa Val (Rubiaceae), namely, psyle A, C, and E have been identifed [91], although other rubiaceous genera contain cyclotides [92,93] reports of possible cytotoxicity and chemo sensitization of cyclotides from Psychotria are lacking.Cycloviolacin O 2 isolates exhibited cytotoxic efect [80], due to their chemical components and structure [94,95].Cyclotide A and kalata B1 have been studied in diferent works to demonstrate its chemotherapeutic activity [96].Membrane disruption is a mechanism of cyclotide cytotoxicity evident by liposomal and whole tumor cells leakage [97], while kalata B1 acts like a channel through the membrane [98].NMR analysis revealed the hydrophobical binding of cyclotides to surface membranes [99].Tese reports altogether indicate that the primary structure of cyclotides and changes in membrane composition infuence their bioactivity and membrane affnities [100].Breast cancer cell lines have been studied to establish the antitumor activities of cyclotides.In vivo toxicity and antitumor studies of cycloviolacin has also been described [101].

Antihypertensive and Antidyslipidemic Activities.
Anaesthetized rats administered hydromethanolic extract of Viola odoratadose-dependently caused a reduction in blood pressure [102].Hydromethanol extract of common Viola leaves has been demonstrated for antihypertensive and vasorelaxatory efects in vivo studies.Total cholesterol, lowdensity lipoprotein, and atherogenic index were reduced upon treatment with the extract in diet-induced atherogenic rats.Tere was a signifcant increase and decrease in highdensity lipoprotein, body weight, no signifcant diference in glucose, and triglyceride levels, a signifcant reduction in body weight was observed.Te efcacy of this extract was confrmed by the improvement in hypertensive and dyslipidemia conditions and weight loss.Multiple pathways mediate the vasodilator efect of V. odorata extract e.g., efect on Ca 2+ and NO-mediated pathways.A pharmacologic rationale describing the use of V. odorata in lipid disorder treatment and hypertensive conditions exploring the phytochemicals present in Viola has been reported [103].Inhibition of pancreatic lipase activity by saponins has been reported to cause a decrease in dietary fat absorption and increased fat removal in high fat diet fed mice [104].Atherogenic index describes the risk of developing coronary heart disease, a reduction in atherogenic index was observed upon administration of the plant extract [105].Te plant extract was able to reduce some lipid profle parameters and compared favorably with the standard drug; atorvastatin, that acts by inhibiting the activity of HMG Co-A reductase [106].

Anti-Infammatory Activity.
Viola difusa extract showed anti-infammatory activity against dimethylbenzeneinduced ear edema in ear and carrageenin-induced toe tumors in rats [107].Viola mandshurica ethanolic extract signifcantly decreases proinfammatory cytokines and immunoglobulin E and other parameters studied in mice serum [108].Anti-infammatory activity of aqueous extract of V. odorata have been described, the mechanism may be because it can prevent infammatory proliferation [109] because of the water soluble polysaccharides it contains [109].Te activity of V. odorata aqueous extract had prophylactic efects in formalin-induced lung damage in rats by signifcantly caused a decrease in lung infammatory parameters was observed [110].Anti-infammatory drugs: VBHF primarily releases serotonin and histamine to prevent infammation.Tis suggests that the plant may have antiasthmatic, antitussive, and bronchodilator activities.Tis substantiates the well-known folk uses of this plant [111].

Evidence-Based Complementary and Alternative Medicine
Te plant is popularly also known to be used internally and externally, for skin disorders treatment, pain, infammation, and injuries from burn [112].Many compounds such as Violaxanthin, favonoids, saponins, alkaloids, tannins, auroxanthin, favoxanthin, salicylic acid, and polyphenols have been reported in this plant [113].Moreover, antioxidant favonoid compounds, especially rutin are considered responsible for most of heartsease's biological activities of Viola tricolor [114].Te investigation of the topical efect of Viola tricolor in a model of burn injury is important and necessary to confrm its anti-infammatory efcacy.Te healing process of Viola tricolor gel in treating microbial infection may be due to the low pH which prevents the release of some proinfammatory cytokines [115], as well as temperature [116].Viola tricolor is able to keep the gel form because of the polysaccharide [117].

Antipyretic Activity and Management of Pain.
Te possible mode of action of anti-infammatory drugs could also be attributed to the anti-infammatory activity displayed by antipyretic drugs such as paracetamol [118].Yeastinduced rectal temperature of mice was signifcantly reduced upon intraperitoneal administration of VBME.VBME can thus be postulated to contain prostaglandin inhibitory components such as salicylic acids [119].Tis antipyretic action was also demonstrated in the nonpolar fraction of V. odorata [120].
One defense mechanism employed by the body to combat infection is to increase the body temperature beyond the normal 36-37 °C.Yeast-induced pyrexia in rabbits was stabilized with n-hexane, chloroform, and aqueous extract of V. odorata leaves.Te n-hexane extract exhibited the highest antipyretic efects than the other extracts [121].In another study, diaphoretic and febrifuge infantile disorder as well as lung trouble was managed using V. odorata [122] establishing the role of analgesic efects of V. odorata.Salicylic acid, a known sedative agent found in V. odorata evidently showed positive analgesic efects at 400 mg/kg aqueous and methanol extracts of V. odorata.Te results obtained from the study compared favorably with other standard analgesic drugs examined.Te analgesic efects observed in the extracts may be due to inhibition of pain response receptors or pathways leading to the production of infammation [121].

Antihepatotoxic and Antinephrotoxic Activities.
Tere was observed protective activity of methanolic extract of V. difusa by preventing degeneration, necrosis, fbrosis, types I and III collagen expression, a-SMA, and TGF-b1 in the liver when induced with CCl4 [123].Qadir et al. [124] demonstrated the hepatoprotective activity of aqueous extract of V. odorata against paracetamol-induced liver injury in mice.Several phytochemicals such as alkaloids, phytosterols, phenols, carotenoids, and organosulfurs have been identifed from sweet violet blossom powder [103,125,126].Research fndings reported that these phytochemicals may be one of the factors responsible for the observed hepatoprotective role such as in the reduction of liver enzymatic activities [127], favonoid inhibition of bile acid uptake by the hepatocytes [125], reduced bilirubin concentration upon pretreatment with favonoids, favonol glycoside reduction of serum AST, ALP and ALT activities, and in vitro favonoids suppression of elevated levels of GOT and GPT, decreased hepatocyte damages and high antioxidant activity [128].Viola odorata stem, fowers, and leaves are reportedly used in the treatment of respiratory, anti-infammatory, tumor, urinary, liver, and kidney diseases.Animal diet supplemented with sweet violet blossom powder (SVBP) at doses of 0.2-1.6 g/100 g reportedly caused a decrease in the serum AST, ALP, and ALT activities, lipid peroxidation biomarker (malondialdehyde) levels as well as the concentration of some kidney markers such as urea and creatinine [129].Te decrease in serum concentrations of creatinine and uric acid due to feeding with plant parts of sweet violet could be adduced to the high phytochemicals' contents.Research fndings reported that the possible efect of sweet violet may be due to the polyphenols content [128].Tere are reports that explained that favanone protect and maintains the kidney functionality by reducing serum urea and creatinine concentrations, excessive urination leading to loss of sodium ion and improved body weight [130,131].5.9.Insecticidal Activity.Cycloviolacin O2, O3, O8, O13, 14, 15, and 16 isolated from V. odorata have been identifed as insecticidal agents [132].Viola odorata essential oil also possesses repelling efect against culex, aedes, and anopheles mosquito strains [133].Evidence has been shown that cyclotide kalata B1prototype possesses insecticidal activity [134].A sixteen (16) day feeding period with kalata B1 supplement (0.825 μmol/g diet) recorded a nonsurvival rate of half of the experimental Helicoverpa punctigera larvae population.Control and treatment diets showed a signifcant growth pattern diference in H. punctigera.Digestive enzyme inhibition by plant-based defense proteins has been proposed as a possible mode of action for the observed insecticidal activity [135].Kalata B1 and B2 were discovered not to be responsible for the enzyme inhibitory role seen in mammalian and insect trypsins and chymotrypsins as well as α-amylase activity in Helicoverpa gut [134].Insecticidal activity of cyclotide f-Viola is yet to be reported.

Treatment of Respiratory Disorders.
Complementary system reactivation with reduced proinfammatory markers production was observed in a study of the protective role of V. yedoensis petroleum ether extract in the lung.Te downregulation of interleukin-1b (IL-1b), interleukin-6 (IL-6), and tumor necrosis factor-a (TNF-a) together with complementary reaction alleviation could be possible for the displayed extract activity in the protection of the lungs from acute injury [136].Cough, infammation, pain, infections, and sleep disturbance have been reported to be efectively managed by V. odorata.Mucilages are protective substances that cover the mucosal membranes of the mouth, throat, and larynx, thus preventing them from various respiratory and infammatory diseases and so on [137].Te properties of mucilage and their high amount in V. odorata fowers and leaves serve as emollient and demulcent, hence their use in 8 Evidence-Based Complementary and Alternative Medicine the preparation of medicaments for respiratory and gastrointestinal diseases [138].Climatic conditions have a large infuence on the therapeutic role performed by plants.Viola odorata is found in cool regions and hence suitable for the treatment of heat and/or dry related ailments these include fever, cough, or respiratory infections as believed traditionally [121].Te cooling efect of V. odorata leaves was used internally by dioscorides (IV 121) for treating eye infammation, heartburn, and prolapse of anus and its purple fowers externally for sore throat and epilepsy in children.Respiratory related diseases afect either the lower respiratory chamber (e.g., pneumonia) or the upper respiratory chamber (e.g., common cold, sinusitis tonsillitis, laryngitis, and pharyngitis).Te disease conditions range from mild, such as common cold to severe such as asthma, allergies, sinusitis, and so on.Viola odorata is mainly used for skin infections, rheumatism, or urinary tract infections can also be used to cure catarrh, common cold, and cough [139].
5.11.Immunomodulation Activity.Viola yedoensis, V. difusa, and V. tricolor aqueous extracts have been reported to exhibit signifcant immunomodulatory efects [48,107].Te Violaceae, particularly Viola tricolor, have been noted as rich cyclotide (natural cyclic peptides) sources [90].Cyclotides are plant compounds synthesized in the ribosomes [140], and they display unique structural cyclic backbones with three disulfde bond arrangement knotted to confer remarkable stability in them [141,142].Cyclotides were recently reported to block T-lymphocyte proliferation by acting as immunosuppressive peptides [143].Peptidecontaining Oldenlandia afnis DC. (Rubiaceae) plant extracts previously demonstrated an immunosuppressive effect towards activated human lymphocytes [144], with kalata B1 cyclotide identifed as a key compound of Oldenlandia afnis exhibiting the immunosuppressive efect [48].Te observed immunosuppressive efects may be due to cyclotides-rich content of V. tricolor.Hence, the efect of Viola extract against proliferating cells showed the presence of cyclotides when identifed using HPLC, LC-MS, and MALDI-TOF analysis.Purifed kalata B1 isolated from Oldenlandia afnis and synthetic kalata B1 analogs were able to reduce T-cell poly functionality, stalling immunecompetent cell proliferation by blocking IL-2 biology at various sites [143].Cyclotides caused a further decrease in the expression of marker of IL-2 cell surface [143].Tere is a wide range of diferent immunologic properties.Evidence has shown that Viola extract exert numerous IL-2 biologic and degranulating efects probably due to the multifunctional cyclotide components, although it did not display efect on IL-2 receptor expression [144].Te immunosuppressive properties as well as the side efects of V. tricolor in a low immunity individual need to be assessed [48].
5.12.Activity on Neurological Disorder.Animal studies have been used to evaluate the neurological efects (such as presedative and sedative) of Viola.Chloroform-methanolic (70 : 30) extract of Viola demonstrated a higher presedative and sedative efect than diazepam; the reference drug [145].Te analgesic efect of aqueous and methanolic extract of V. odorata in rats employing the tail immersion test and hot plate test showed signifcant efectiveness in peripheral and central models of pain [146].Moreover, nasal drop administration of violet oil for a period of 1 month in patients with insomnia resulted in improved insomnia and sleep [147].Te numerous therapeutic roles displayed may be adduced to the various bioactive components.Tere are diferent formulations of common violet in the treatment of internal diseases, these include as pills and syrups linctus (Laooq; is prepared specifcally for the respiratory tract) forms.To enhance efectiveness, multiple natural ingredients could be added [148].Te polyphenolic content of common violet has valuable efects on the nervous system and its potent antioxidant and neuroprotective roles [149].Te essential oil of common violet has been shown to contain a monoterpene called linalool as its main ingredient, which is shown to possess a hypnotic efect when inhaled in animal model studies, but its hypnotic efect does not afect the coordination of motor.Linalool was reported to also exhibit sedative and anticonvulsant activities in experimental mouse models [150].Sedative efect is nontoxic to the neuron but the ethyl acetate fraction of V. tricolor at high concentration can cause pentobarbital hypnosis which may be due to the component(s) of the fraction [151].

Neurotensin Antagonism.
Only one cyclotide of known neurotensin antagonistic potential has been reported, although others may not have been documented for this property.Cyclopsychotride A upon screening assay at IC 50 of 3 μM inhibited the binding of neurotensin to the cell membrane of HT-29 carcinoma in human [92].Te functional antagonistic and neurotensin-induced high HT-29 levels in the cytosol efects of Ca 2+ were examined.An increase in intracellular concentration of Ca 2+ in a dosedependent fashion which was however not inhibited by any known neurotensin antagonist was seen.Te reported neurotensin antagonist, cyclopsychotride A is believed to display its antagonistic activity through a diferent receptor [92].Te mechanism by which cyclopsychotride A increases Ca 2+ concentrations in the cytosol of diferent cell lines that are nonexpressive of neurotensin receptors is yet to be reported.

Typical Doses
Tree times daily intake of 2-4 g dried herb was recommended by British herbal pharmacopeia [152] and 1 g daily dose oral administration of root in physician's desk reference (PDR) [153].Viola odorata has been recommended by the Iranian traditional medicine with a permissible maximum dose of 250 mg/kg containing 20 g dry fower/dose for the treatment of cough, rectal prolapse, and febrile convulsion in children.Experimental rabbits also exhibited high tolerance of the extract at an oral dose of 1.6 g/kg, no mortality was recorded [154].Gastroenteritis, vomiting, stomachache, nervousness, and depression may be observed Evidence-Based Complementary and Alternative Medicine when the recommended dose of 5-7 g is exceeded [155].Clinical trials of sweet violet or its interaction with supplements have not been proven, likewise its efect on pregnancy and lactation [156].

Cytotoxicity
Tere are no observed health hazards or side efects at the appropriate therapeutic doses [153].Acute toxicity test after forty-eight (48) hours oral administration of 10 ml/kg of 1, 3, and 5 g/kg doses of violet leaf extract in BALC/c mice showed no toxic efect; there was no recorded lethargy, death, changes in behavior [103].Toxicity studies after 24 hours oral administration showed that organic solvents (methanol, butanol, and n-hexane) and aqueous extracts of violet are nontoxic at 2000 mg/kg [72].Another study revealed the cytotoxic efect of V. tricolor is exhibited by three cyclotides [157].

Conclusion and Future Perspective
Plants of this genus have long been used by traditional healers for the management and treatment of several human diseases including diabetes, asthma, lung diseases, fatigue, and several other diseases.Te plants of the genus have also received scientifc validation of their pharmacological activities including neuroprotective, immunomodulatory, antimicrobial, antiparasitic, anticancer, antihypertensive, antidyslipidemic, analgesic, antipyretic, diuretic, antiinfammatory, anthelmintic, antioxidant, and anti-HIV.
Viola is highly rich in diferent bioactive compounds and essential oils.Tis review harnesses some of the identifed compounds as well as the pharmacological activities of Viola.
In addition, this review provides a guide for further studies into the pharmacokinetics of this genus.Reliable pharmacokinetic profles in animals and humans would be crucial for a better understanding of the systemic behavior of Viola species.In the future, the other local uses of this genus need to be investigated; the chemical and biological relationships of these species should also be studied to expand the medicinal resources and standardize the use of Viola species.

Table 1 :
Chemical constituents of some species of Viola.

Table 2 :
Summary of compounds identifed in the essential oil of some Viola species.